Gastrointestinal dysfunction occurs frequently in patients with traumatic brain injury (TBI). More than 50% of patients with severe head injuries develop gastrointestinal dysfunction. Failure to maintain gastrointestinal function is a significant cause of post-trauma morbidity and mortality. The association of severity of brain injury with gastrointestinal dysfunction suggests a strong link between the central nervous system and the gastrointestinal system. However, whether alterations in the gastrointestinal system are involved in modulating neuronal damage and recovery after TBI is largely neglected. In this proposal, we will focus on the role of a gastrointestinal hormone, ghrelin, in the development of brain injury after TBI. Ghrelin was originally reported to induce growth hormone release through stimulation of ghrelin receptors in the central nervous system. However, a large body of evidence has indicated other physiological functions of ghrelin mediated by the central and peripheral ghrelin receptors. Recent studies have demonstrated that ghrelin is a vasoactive peptide and possesses anti- inflammatory properties. A major event following brain trauma is the loss of autoregulatory capacity of brain microvessels which results in sustained hypoperfusion and improper delivery of vital metabolites to the brain tissue. Moreover, TBI initiates a cascade of inflammatory processes that can serve to exacerbate the initial injury. However, the role of ghrelin in the development of brain injury after TBI remains unknown. Using a rat model of TBI induced by weight drop, we have shown that ghrelin gene expression in the stomach is significantly reduced after TBI and central ghrelin blockade through intracerebroventricular injection of ghrelin receptor antagonists exacerbates brain injury after TBI. We therefore hypothesize that downregulation of ghrelin contributes to the sustained hypoperfusion and exaggerated inflammatory responses, and subsequently exacerbates the initial injury after TBI. We will first determine the correlation of the kinetic profiles of ghrelin and ghrelin receptor expression with brain injury after TBI and then determine the effect of central ghrelin replacement on brain injury following TBI. Uncoupling protein-2 (UCP2) prevents neuronal death and diminishes brain dysfunction after brain trauma. Ghrelin has been shown to enhance UCP2 expression in various organs including the brain. Thus, we hypothesize that ghrelin attenuates brain injury via upregulation of UCP2 after TBI. We will determine the effects of ghrelin on cortex and hippocampus UCP2 expression in TBI animals and compare ghrelin's effects on brain injury and neurological outcome in wild-type and UCP2 knockout mice following brain trauma. Collectively, the proposed studies will provide novel mechanistic information about the pathophysiology of TBI, and may lead to the development of a new therapeutic intervention for patients with brain injury. PUBLIC HEALTH RELEVANCE: Traumatic brain injury (TBI) represents a major health care problem and a significant socioeconomic challenge worldwide. In the United States alone, approximately 2 million patients are affected each year, and the mortality of severe TBI remains as high as 35%-40%. These statistics underline the urgent need for efficient treatment modalities to improve posttraumatic morbidity and mortality. The relevance of this proposal to public health is to eventually use ghrelin in the treatment of patients with head injury.